Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: Multiple different phenotypes associated with an inactivatingAlu insertion mutation of the calcium-sensing receptor gene

Abstract

Neonatal severe hyperparathyroidism (NSHPT) is considered an autosomal-recessive disorder, attributable in many cases to homozygous inactivating mutations of the Ca++-sensing receptor (CASR) gene at 3q13.3-21. Most heterozygotes are clinically asymptomatic but manifest as familial (benign) hypocalciuric hypercalcemia (FHH) with a laboratory profile that is variably and sometimes only marginally different from normal. In 5 NSHPT cases from 3 Nova Scotian families, we found homoallelic homozygosity for an insertion mutation in exon 7 of CASR that includes an Alu repeat element with an exceptionally long polyA tract. Four of the 5 NSHPT infants were treated by parathyroidectomy more than a decade ago and are well now. A fifth went undiagnosed until adulthood and has profound musculoskeletal and neurobehavioral deficits. Among 36 identified FHH heterozygotes are 3 individuals with an unexpected degree of hypercalcemia and elevated circulating parathyroid hormone levels consistent with secondary hyperparathyroidism. Two are obligately heterozygous offspring of NSHPT mothers with surgical hypoparathyroidism and variable compliance with vitamin D therapy. The other is an adult with coexistent celiac disease in whom hyperparathyroidism, probably secondary to vitamin D deficiency, led to surgery. In counseling affected families, the heterozygous state should not be considered entirely benign, since FHH heterozygotes, particularly infants, may be prone to secondary hyperparathyroidism and symptomatic hypercalcemia. In such families, molecular diagnosis will allow for unambiguous identification of at-risk individuals.

Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations

“…Early diagnosis is critical as untreated NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy to alleviate the hyperparathyroidism and hypercalcaemia. 65 As noted earlier, the most severe cases of NSHPT develop ribcage deformities, as well as rachitic changes, skeletal undermineralization, and fractures of the long bones and other skeletal sites. 64,67…”

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

“…In some cases total parathyroidectomy has been combined with autotransplantation of parathyroid tissue. This, however, also carries a high risk of recurrence of hyperparathyroidism, which may persist despite multiple surgical attempts to remove autotransplanted tissue (74,82). Therefore, total NSHPT, neonatal severe hyperparathyroidism; NHPT, neonatal hyperparathyroidism; CASR, calcium-sensing receptor; AP2S1, adaptor-related protein complex 2 sigma 1 subunit; diagnosis, parameters at the time when the diagnosis was made; age at 1st symptoms; age at which specific disease manifestations of NSHPT or NHPT were documented; y, years; m, months; w, weeks; d, days; S-Ca, total serum calcium; (ion) denotes ionized serum calcium; S-PTH, serum parathyroid hormone; S-PTH min, minimal S-PTH after therapy; decrease of S-Ca; Y; yes, N, no; # , mutants tested sensitive in vitro (see Table 4); minimal effective dose, minimal dose at which a decrease of serum calcium or PTH was reported; * , maximum dose used in patients without response; NR, not reported.…”

“…An unresolved issue is the serum calcium level one should aim for in these patients with a ubiquitously and severely impaired CASR function. 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. 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.…”

Physiology and pathophysiology of the calcium-sensing receptor in the kidney

“…NSHPT is most commonly caused by homozygous (58,125,126) or, rarely, compound heterozygous mutations in the CaSR gene (85) (in the latter, an infant inherits one inactivating CaSR mutation from one parent and a second from the other). There is relative or absolute hypocalciuria in NSHPT (30,104), although Ca 2ϩ excretion can be elevated in some cases, presumably owing to the markedly increased filtered load of Ca 2ϩ . Early diagnosis is critical, as untreated NSHPT can have a fatal outcome or severe impairment of subsequent mental, skeletal, and somatic growth without parathyroidectomy to alleviate the hyperparathyroidism and hypercalcemia (30,61).…”