Familial Hypocalciuric Hypercalcaemia: Association With Neonatal Primary Hyperparathyroidism, and Possible Linkage With Hla Haplotype

Abstract

A kindred is described, six members of which fulfilled criteria for the syndrome of familial hypocalciuric hypercalcaemia (FHH). The majority of these individuals were asymptomatic: their hypercalcaemia was revealed by biochemical screening after parathyroid surgery had failed to diminish the elevated serum calcium concentration of the index case. In contrast to those members of the family diagnosed as adults, the daughter subsequently born to the index case included in her expression of FHH clinical features of severe neonatal primary hyperparathyroidism. Four hyperplastic parathyroid glands were excised, and following surgical intervention the baby improved clinically and accelerated the healing of her skeletal lesions. Her case suggests that an association does exist between FHH and neonatal primary hyperparathyroidism. Of the ten individuals at risk, inheritance of hypocalciuric hypercalcaemia was paralleled in eight cases by inheritance of the HLA haplotype All BW55 CW3 DR4. Such possible linkage has not previously been reported.

In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia.

“…If the set-point of the fetal parathyroids is increased, the fetus will sense in cord blood as abnormally low, thereby producing some degree of secondary hyperparathyroidism on top of the already abnormal set-point of the fetal parathyroids. This hypothesis is borne out by the observation that in all 10 of the reported cases of NHPT in children with one FBHH parent the affected parent has been the father (3,7,(14)(15)(16)(17)(18). Indeed, patient A-26 in the kindred with the same R185Q mutation (30) as in our patient inherited the abnormal CaR allele from her father and was born to a healthy mother (3).…”

“…Marx et al suggested in 1982 that some cases of NHPT might be the homozygous form of FBHH, because children with NHPT were encountered in families with both parents affected by FBHH (3). However, NHPT has also been noted in cases where only one parent had clinically apparent FBHH (3,7,(14)(15)(16)(17)(18), and many further cases of NHPT appear to be sporadic, with both parents being normocalcemic (1,(19)(20)(21)(22)(23)(24)(25)(26). Thus the nature of the genetic defect and how it produces two different hypercalcemic syndromes was obscure.…”

Casting new light on the clinical spectrum of neonatal severe hyperparathyroidism

“…After their parathyroid bone disease has healed, they are left with the benign problem of FBHH. The observation that all of the cases of ‘dominant’ NSHPT have been transmitted from the father with FBHH, adds further weight to this idea ( Spiegel et al ., 1977 ; Thompson et al ., 1978 ; Sopwith et al ., 1984 ; Fujimoto et al ., 1990 ; Wilkinson & James, 1993; Page & Haddow, 1997). In these ‘paternally transmitted’ cases, as with the de novo mutations ( Pearce et al ., 1995 ; Bai et al ., 1997 ), the fetus with a heterozygous CaR inactivation gestated in a normocalcaemic (rather than hypercalcaemic) mother, appears to be most at risk of developing secondary hyperparathyroidism.…”