Neonatal Severe Primary Hyperparathyroidism Research Articles

Parathyroid hormone-dependent hypercalcemia

The past fifteen years have resulted in great progress in our understanding of the pathogenesis and pathophysiology of hypercalcemic disorders occurring either sporadically or in a familial setting. This paper briefly reviews the clinically most important new knowledge on sporadic and hereditary forms of parathyroid hormone-dependent hypercalcemic disorders, with special emphasis on familial syndromes such as multiple endocrine neoplasia type 1 and type 2A, hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia and neonatal severe primary hyperparathyroidism. In addition, the authors briefly present the most important clinical characteristics of 141 patients with parathyroid hormone-dependent hypercalcemia, including index patients of 18 families with hereditary disorders, diagnosed in a Hungarian endocrine center between 1997 and 2007.

Unusually severe phenotype of neonatal primary hyperparathyroidism due to a heterozygous inactivating mutation in the CASR gene

We present a male patient with neonatal severe primary hyperparathyroidism, whose manifestation was exceptionally serious for the heterozygous inactivating mutation he carried in the CASR gene. The patient presented soon after birth with respiratory distress requiring long-term mechanical ventilation, bone and chest deformities, feeding problems, and hypotonia. He had hypercalcaemia, hypophosphataemia, and hyperparathyroidism. There was no known history of calcium metabolism disorders in the family. As the impact on calcaemia of a rescue therapy with bisphosphonates was only transient, a subtotal and subsequently total parathyroidectomy were performed in the fourth month of life. Afterwards his clinical status improved and the fractures healed, but his neuropsychological development is delayed due to cerebral atrophy. Genetic analysis revealed a heterozygous missense CASR mutation R185Q, and an approximately equal expression of the mutated and wild-type RNA in the parathyroid tissue. The mother of the child was homozygous for the wild-type allele; the father is unknown. In conclusion, this patient demonstrates how serious neonatal hyperparathyroidism can be when caused by a heterozygous mutation. This may be attributable to a combination of dominant-negative action of the mutant allele with an intrauterine foetal hyperparathyroidism developed in the mother's normocalcaemic environment, further aggravated by a putative maternal vitamin D deficiency during pregnancy.

Genotype and phenotype correlation of calcium-sensing receptor variants

Mutations of the calcium-sensing receptor (CaR) gene give rise to disorders of renal calcium excretion. It is now demonstrated that even common variants of CaR can cause alteration in tissue sensitivity to extracellular calcium and are associated with primary hypercalciuria. Agents targeting these functional domains may well be an option for the management of hypercalciuria and renal stones.

Diseases associated with the extracellular calcium-sensing receptor

The human calcium-sensing receptor (CaSR) is a 1078 amino acid cell surface protein, which is predominantly expressed in the parathyroids and kidney, and is a member of the family of G protein-coupled receptors. The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium reabsorption in response to alterations in extracellular calcium concentrations. The human CaSR gene is located on chromosome 3q21.1 and loss-of-function CaSR mutations have been reported in the hypercalcaemic disorders of familial benign (hypocalciuric) hypercalcaemia (FHH, FBH or FBHH) and neonatal severe primary hyperparathyroidism (NSHPT). However, some individuals with loss-of-function CaSR mutations remain normocalcaemic. In addition, there is genetic heterogeneity amongst the forms of FHH. Thus, the majority of FHH patients have loss-of-function CaSR mutations, and this is referred to as FHH type 1. However, in one family, the causative gene for FHH is located on 19p13, referred to as FHH type 2, and in another family it is located on 19q13, referred to as FHH type 3. Gain-of-function CaSR mutations have been shown to result in autosomal dominant hypocalcaemia with hypercalciuria (ADHH) and Bartter’s syndrome type V. CaSR auto-antibodies have been found in FHH patients who did not have loss-of-function CaSR mutations, and in patients with an acquired form (i.e. autoimmune) of hypoparathyroidism. Thus, abnormalities of the CaSR are associated with three hypercalcaemic and three hypocalcaemic disorders.

Clinical review 109: Contrasting paradigms for hereditary hyperfunction of endocrine cells.

Hereditary endocrine hyperfunction is categorized here as neoplastic or not neoplastic. The disorders and their mutated genes are subdivided further by hyperfunctional hormone secretory tissue (Table 1). For example, the parathyroids hyperfunction in at least three hereditary neoplastic syndromes [multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2a (MEN2a), and hyperparathyroidism-jaw tumor syndrome (HPT-JT)], each associated with one distinct gene (1, 2) or locus (3–5). Alternately, the parathyroids can be overactive in two hereditary non-neoplastic syndromes–familial hypocalciuric hypercalcemia (FHH) or neonatal severe primary hyperparathyroidism (NSHPT). Either is usually caused by mutations of the CaSR gene (6–9); two other undiscovered genes account for FHH in a few families (10, 11). A similar classification dichotomy applies to hereditary hyperfunction of pancreatic islet b cells (1, 12–17), of thyrocytes (18–23), or of Leydig cells (19, 24–26) (Table 1). For didactic purposes, this analysis omits endocrine tissue without separate hereditary disorders in each of the two categories. For example, hereditary pheochromocytoma may arise from neoplasia with germline mutation of VHL (12), RET (2), or NF1, but apparently not from non-neoplastic processes. This analysis also excludes dysfunctions outside the hyperfunctional endocrine tissue (for example, hereditary hyperandrogenism can be caused by activation of the CRF/ACTH axis secondary to defective cortisol synthesis).

Disorders of the calcium-sensing receptor

The human calcium-sensing receptor (CaSR) is a 1078-amino-acid cell surface protein which is expressed in the parathyroids, thyroid cells and the kidney, and is a member of the family of G protein-coupled receptors. The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium reabsorption in response to alterations in extracellular calcium concentrations. The human CaSR gene is located on chromosome 3q13.3–q21, and loss of function CaSR mutations have been reported in the hypercalcaemic disorders of familial benign (hypocalciuric) hypercalcaemia (FBH or FHH) and neonatal severe primary hyperparathyroidism (NSHPT). In addition, gain of function CaSR mutations have been observed in a novel familial syndrome of hypocalcaemia with hypercalciuria. The human CaSR gene on chromosome 3q13.3–q21 is likely to be one of several, as two other loci for FBH have been located on chromosome 19p and 19q13. Cloning and characterisation of these genes will help to further elucidate the mechanisms regulating extracellular calcium.

Genetic abnormalities in sporadic parathyroid adenomas: loss of heterozygosity for chromosome 3q markers flanking the calcium receptor locus.

Inactivating mutations of the parathyroid cell calcium receptor (CaR) gene cause one form of familial benign/hypocalciuric hypercalcemia, and in homozygous form, cause neonatal severe primary hyperparathyroidism with parathyroid hyperplasia. Thus, we postulated that partial or total loss of CaR function might contribute to calcium insensitivity or even stimulate cell proliferation in sporadic parathyroid adenomas (PAds). To examine this possibility, we sought loss of heterozygosity (LOH) for markers flanking the CaR locus (3cen-3q21) in 35 PAds. We used 16 highly-polymorphic PCR-based markers in paired normal and tumor DNA, extracted from slices of archived surgical specimens. Nineteen to 24 of the DNA pairs were informative with at least one marker. In two informative pairs, we found LOH for markers D3S1303, D3S1267, or D3S1269, which are tightly-linked with and flank the CaR locus. In one tumor, deletion mapping confined the lost area between D3S1271 and D3S1238 (41.7 centimorgans, cM). In the other tumor, LOH spanned most of chromosome 3, ranging at least from D3S1307 to D3S1311 (271.4 cM). LOH was confirmed by repetition of the experiments and quantified by phosphorimaging. Thus, we found LOH encompassing the CaR locus in approximately 10% of sporadic PAds. These data are consistent with the hypothesis that loss of CaR function may occur in PAds, with functional consequences for calcium sensitivity and cell proliferation.

Familial hypocalciuric hypercalcemia. Mild expression of the gene in heterozygotes and severe expression in homozygotes

Autosomal dominant familial hypocalciuric hypercalcemia was found in a kindred with neonatal severe primary hyperparathyroldism, previously judged to be an autosomal recessive trait. Mild hypercalcemia was documented In eight members representing three generations. Mild hypercalcemia was documented at an age as early as one week. In seven adults presumed to be heterozygotes, urinary calcium levels were in the same range as for familial hypocalciuric hypercalcemia. An additional adult member (who previously underwent parathyroidectomy for neonatal severe primary hyperparathyroidism) showed an abnormality in renal clearance of calcium and sodium characteristic of combined familial hypocalcluric hypercalcemia and surgical hypoparathyroidism. Parathyroldectomy in three hypercalcemic members did not cause normocalcemia. Unlike other kindreds with familial hypocalciuric hypercalcemla In whom hypercalcemia is consistent over time and moderate in heterozygotes, this kindred was characterized by heterozygotes showing hypercalcemla that was intermittent and mild. The consanguineous parents of the two previously described severely affected neonates were judged to be heterozygotes for familial hypocalcluric hypercalcemia. In conclusion, (1) a gene presenting as familial hypocalciuric hypercalcemla can be expressed as hypercalcemia that is intermittent and very mild in heterozygotes; (2) such a gene can cause neonatal severe primary hyperparathyroldism in homozygotes.