A novel mutation in the calcium-sensing receptor gene in an Irish pedigree showing familial hypocalciuric hypercalcemia: a case report
Buyl Journal of Medical Case Reports
A novel mutation in the calcium-sensing receptor gene in an Irish pedigree showing familial hypocalciuric hypercalcemia: a case report
Wael F Elamin 0 1
Olivier de Buyl 1
0 Elrazi College of Medical Sciences and Technology , Khartoum , Sudan
1 Bantry General Hospital , Bantry, Co. Cork , Ireland
Introduction: Familial hypocalciuric hypercalcemia is a rare autosomal dominant disorder characterized by asymptomatic and non-progressive hypercalcemia due to mutations of the calcium-sensing receptor gene. Disorders of calcium metabolism are very common in the elderly, and they can coexist with familial hypocalciuric hypercalcemia in affected families. Case presentation: We describe an Irish family with hypercalcemia and hypocalciuria. The proband, an 80-year-old Irish woman, presented with hypercalcemia, relative hypocalciuria, and an elevated parathormone level. She also had chronic kidney disease stage 3 and vitamin D deficiency. Two of her sons were also found to be hypercalcemic and hypocalciuric. DNA sequencing identified a novel missense inactivating mutation in the calcium sensing-receptor gene of the proband and her two hypercalcemic sons. Conclusion: Familial hypocalciuric hypercalcemia due to a novel mutation in the calcium-sensing receptor gene was diagnosed in the proband and her two sons. Disorders of calcium metabolism can be multifarious in the elderly. We suggest that testing first degree relatives for calcium levels and DNA sequencing may have a role in the assessment of elderly patients with parathormone-related hypercalcemia.
-
Introduction
Familial hypocalciuric hypercalcemia (FHH) is a rare
autosomal dominant disease that runs a benign course.
Its prevalence is not clearly established [1]. It is
important to differentiate it from the much more common
primary hyperparathyroidism (PHPT) to avoid unnecessary
and potentially harmful parathyroidectomy [2]. It has
been shown to result from heterozygous inactivating
mutations in the calcium-sensing receptor (CaSR) gene
in the majority of cases [3]. The calcium sensing receptor
(CaSR) is a G-protein-coupled receptor of 1078 amino
acids (AAs) with a large extracellular domain and the
characteristic seven-transmembrane domains [4]. It is
expressed in the parathyroid gland, kidneys, bones, and
other tissues [5] and plays a key role in the maintenance
of constant levels of extracellular ionized calcium. It
modulates the function of chief cells of the parathyroid
gland, stimulating the synthesis and secretion of PTH as
* Correspondence:
1Bantry General Hospital, Bantry, Co. Cork, Ireland
Full list of author information is available at the end of the article
well as the proliferation of parathyroid cells when the
calcium level is low, and inhibiting these functions when the
calcium level is high. In the kidneys, the CaSR decreases
calcium reabsorption, increases calciuresis, and decreases
the concentrating ability of the kidney when sensing
hypercalcemia, through its effect on the thick ascending
limb of the loop of Henle and on the medullary collecting
ducts [6]. Two hundred and twenty-three mutations for
the CaSR gene are listed in the CaSR mutation database
[7]. Of these, 154 are inactivating (loss-of-function), and
most of them cause FHH in heterozygous and neonatal
severe hyperparathyroidism (NSHPT) in homozygous
patients [3]. Curiously, most of these mutations are
confined to a single family, with only a few having been
described in more than one family. Inactivating
mutations result in decreased sensing of calcium levels,
shifting the calcium-PTH curve and the set-point to the right
[6]. Elderly patients are frequently affected with disorders
of calcium metabolism [8-10]. Here we describe an Irish
family in which the proband is an octogenarian with
hypercalcemia, hypocalciuria, chronic kidney disease
(CKD), and low vitamin D level. Because two of her
children had hypercalcemia and hypocalciuria as well, we
carried out DNA sequencing in the CaSR gene in the
patient and three of her children.
Case presentation
An 80-year-old Irish woman was admitted to our
hospital after the onset of a dense right hemiplegia and
dysphasia. She had been seen in our hospital
previously after an episode of collapse and was diagnosed
with hypertension, atrial fibrillation, congestive heart
failure, epilepsy, and hypercalcemia. She had a past
history of cholecystectomy 33 years earlier. No history
of constipation, anorexia, vomiting, bone pains,
polyuria or polydypsia, or psychiatric or cognitive
disturbance was noted. Her hypercalcemia had been quite
severe, ranging between 3.22 and 3.47 mmol/L, with
albumin levels of 40 g/L on both occasions; the
magnesium level was 0.90 mmol/L (normal, 0.70 to 1.00).
PTH levels in those instances had been measured
between 170 and 235 ng/L (normal, 10 to 55 ng/L).
She was taking no medication at the time of sampling.
Her urine analysis was negative on three occasions.
Arterial blood gases s (...truncated)