An Association between Neonatal Severe Primary Hyperparathyroidism and Familial Hypocalciuric Hypercalcemia in Three Kindreds

Abstract

Four cases of neonatal severe primary hyperparathyroidism occurred in three families; familial hypocalciuric hypercalcemia was present in each kindred. The diagnosis of familial hypocalciuric hypercalcemia was based on the following features; hypercalcemia in many relatives (eight to 16 per kindred), without other features of the multiple endocrine neoplasia syndromes; recognition of hypercalcemia before the age of 10 in one to three relatives; hypocalciuric hypercalcemia in all relatives tested (five to 14 per kindred); and abnormal serum calcium levels despite parathyroidectomy in all additional relatives (one to five per kindred) undergoing this operation. The association of two uncommon syndromes (neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia) in these kindreds suggests that the two syndromes share a common genetic cause within each kindred.

Urinary calcium excretion in familial hypocalciuric hypercalcemia. Persistence of relative hypocalciuria after induction of hypoparathyroidism

“…In some reports, parathyroid glands have been described as histopathologically normal (1,4,32), although a recent detailed histologic analysis of surgical specimens showed that at least 13 of 18 patients with FHH exhibited parathyroid hyperplasia (33). Furthermore, severely symptomatic primary hyperparathyroidism has been documented in neonatal members of three FHH kindreds (13).…”

“…Both the parathyroids and the renal tubules manifest an abnormality of calcium metabolism in FHH; parathyroid gland growth and PTH secretion are not regulated by calcium in a normal fashion (13,33), and the renal tubules, via a process that is independent of hyperparathyroidism, reabsorb an excessive fraction of filtered calcium. A single genetic trait must explain the abnormalities in both organs.…”

“…Criteria (13,14). Urine calcium excretion in 13 of her hypercalcemic relatives was in the range characteristic of FHH (13).…”

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.

“…We refer to this same condition here as familial benign hypocalciuric hypercalcemia (FBHH) in recognition of the contributions of both Foley et al and Marx et al to its clinical description. 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).…”

Severe Hypercalcemia Due to Primary Neonatal Hyperparathyroidism in an 8-Day-Old Neonate: A Case Report

“…It often presents in the first few days of life with severe PTH-dependent hypercalcemia, hypotonia, irritability, failure to thrive, constipation and respiratory distress [5]. The main forms of primary familial hyperparathyroidism presenting in infancy are: 1) autosomal recessive familial parathyroid hyperplasia [6,7]; 2) autosomal dominant familial hypocalciuric hypercalcemia (FHH) [8], resulting from an inactivating mutation of the calcium sensing receptor (CaSR) gene; 3) neonatal severe hyperparathyroidism (NSHPT) in children with homozygous or double heterozygous mutations of CaSR gene; and 4) sporadic neonatal hyperparathyroidism due to de novo heterozygous CaSR mutations [9]. Most of the literature on PHPT in pediatric patients has been limited to case reports and small series.…”