Seven index cases (5F/2M, mean age 53.4y) with CaSR variants were identified, 6 of which had undergone surgical intervention. Six out of 7 could be classified as FHH with identification of new pathogenic or likely pathogenic variants, while the 7th case had a parathyroid adenoma (PA) with a CASR variant that was ultimately classified as variant of uncertain significance (VUS). All had hypercalcemia with inappropriately normal or high PTH 1-84 values (Table 1).
Three patients presented with a classical FHH phenotype. In the first case (1:F-45y), the disease occurred in a context of IgA nephropathy with progressive decline of kidney function. Surgical intervention was indicated after a 5 years follow-up in our nephrology tertiary referral center, where hypocalciuria was misinterpreted as being secondary to chronic kidney disease, in the presence of a single parathyroid abnormality visible on both neck ultrasound (US) and parathyroid scintigraphy. Calcemia was 2.64mmol/L(N:2.20-2.55mmol/L) with high PTH level(68.8pg/ml,N:15-65pg/ml). Minimally invasive surgery was converted to open surgical intervention due to insufficient decrease of intraoperative PTH, and a subtotal parathyroidectomy (PTx) (3 glands removed) was performed.
The second patient (2:M-76y) had a previous history of resection of a parathyroid adenoma. His latest follow-up showed a persistent hypercalcemia (2.65mmol/L) with hypophosphatemia (0.75mmol/L,N:0.81-1.45mmol/L). Calciuria was in the normal range limit (103 and 160mg/day,N:100-300mg/day) and his CCCR (0.017) was inconclusive to differentiate between FHH and PHPT. The patient had renal lithiasis, osteopenia and chronic renal failure stade 2. Neck US and parathyroid scintigraphy were negative. Because of the presumed persistent PHPT with negative parathyroid imaging, a genetic screening was performed. Genetic testing for case 2 revealed the same pathogenic CASR variant as case 1(c.893C>T,p.(Ala298Val))[7], a finding which argued against reoperation.
The third patient (3:M-77y) had a classical FHH biochemical phenotype (calcemia=2.61mmol/L,PTH=70pg/mL,calciuria=72mg/day,CCCR=0.007). Imaging were negative. Genetic testing revealed a CASR pathogenic variant in exon 5(c.1525G>A,p.(Gly509Arg))[11].
Three additional cases had undergone surgical intervention due to a less typical clinical picture with marked hypercalcemia and fluctuating values of calciuria. All of them were relatively young at diagnosis and had negative parathyroid imaging studies despite significant hypercalcemia (2.80,2.90,2.84mmol/L,respectively). Bilateral neck exploration was performed which resulted in resection of two hyperplastic glands in cases 4 and 6, and one hyperplastic gland in case 5. All had persistent hypercalcemia post-operatively. It has to be underlined that the existence of a multiglandular disease, objectivated during cervicotomy, prompted the surgeons to limit the extent of parathyroid resection to prevent the occurrence of post-operative hypoparathyroidism. Genetic counseling enabled the identification of relatives with CASR variants.
In case 4 (F-42y), post-operative calciuria (400mg/24h) and CCCR (0.021) were not decreased. Genetic testing detected a pathogenic CASR variant(c.1664T>C,p.(Ile555Thr))[7,12]. Her daughter, 20y, had a mild hypercalcemia (2.63mmol/L), hypophosphatemia (0.65mmol/L), mild elevated PTH (73pg/mL), normal calciuria (144mg/24h) with a decreased CCCR (0.008). Her son, 18y, had significant hypercalcemia (2.88mmol/L), normal PTH (58pg/mL), normal calciuria (171mg/24h) and a decreased CCCR (0.006). Again, both children had negative parathyroid scintigraphy.
In another patient (5:F-36y) a CASR variant(c.511A>T,p.(Ser171Cys)) was identified. It was present in her mother, her sister, her brother and her niece. followed-up in our institution and has a marked hypercalcemia (2.94mmol/L).
The 6th patient (6:F,52y) had a CASR variant(c.1664T>C,p.(Ile555Thr)). Her brother carried the same variant and had hypercalcemia (2.80mmol/L) with hypocalciuria (68mg/day).
Taken together, these cases (4-6) illustrate that the presence of hypercalcemia in relatives during family screening is very powerful indicator suggesting for the diagnosis of FHH. Negative parathyroid imaging together with marked hypercalcemia and calciuria in the low normal range could also raise the suspicion of FHH.
Finally, the last case (7: F-46y) had typical features of PHPT: calcemia>3mmol/L with a marked elevation of serum PTH 1-84 (629pg/ml), hypophosphatemia (0.74mmol/L) and a normocalciuria (234mg /day) with a high CCCR (0.026). Work-up revealed an osteopenia, a stage 3 renal insufficiency with normal kidney ultrasound. Neck US and parathyroid scintigraphy were concordant for a left P4-derived adenoma. A large left P4 adenoma, i.e adenoma on left superior parathyroid gland (weight:580mg), was resected via minimally-invasive surgery with a significant decline in intraoperative PTH 1-84. Genetic testing revealed an unknown CaSR variant in exon 3(c.347C>T,p.(Ala116Val)) classified as VUS. Phosphocalcic imbalance was normalized following surgery. Although, we could consider in the present case that CASR may be not involved in the patient’s pathology, physicians should be aware that this rare variant may be not always pathogenic.