The severity of the clinical picture in this case including intrauterine fractures was unusual. Classical FHH due to a heterozygous loss of function (LOF) mutation of the CaSR can go unrecognized for years and only rarely is diagnosed in the neonatal period. However, heterozygous forms of FHH with overt neonatal bone disease are described in the literature and are typically defined as NHPT [5–7, 10]. Possible causes of the more severe phenotype seen in these cases include the specific type of CaSR gene mutation, paternal versus maternal inheritance, prematurity and maternal vitamin D deficiency [4, 8].
CaSR mutation type
The exact mechanism of how CaSR activation directs intracellular signaling leading to inhibition of PTH secretion and increased reabsorption of calcium in kidneys remains unknown . It is known that the CaSR functions on the cell surface as a homodimer . Inactivation of the CaSR gene can be caused by missense, nonsense and splice –site mutations . The latter two types of mutations lead to truncated CaSR proteins lacking transmembrane or intracellular domains. These proteins cannot dimerize with the wild type CaSR proteins. As a result, in the heterozygous state, calcium sensing will be limited to the 50% structurally normal receptors. CaSR proteins affected by missense mutations can dimerize with the wild type CaSR protein but lead to a malfunctioning heterodimer. In rare instances, the missense mutations may exert a dominant negative effect leaving a minority of wild-type CaSR homodimers functional . Thus, in our case, the presence of a missense mutation may have contributed to the more severe clinical picture but functional studies would be required to further substantiate this possibility. It is important to note that a point mutation in the same codon which also led to an I555T missense change was reported in a patient with FHH and was not present in 94 control patients .
Paternal vs. maternal inheritance
Maternal serum calcium, which is actively transported through the placenta in the third trimester to maintain a maternal-fetal gradient, impacts fetal calcium metabolism. An infant with a maternally inherited mutated allele will have a more benign clinical picture than an infant with a paternally inherited mutated allele because the resulting mild maternal hypercalcemia helps to activate the mutated fetal CaSR  and inhibit expression PTH secretion. Conversely, in an infant with a paternally inherited mutated allele, the normocalcemic maternal environment can lead to intrauterine fetal hyperparathyroidism as higher calcium levels would be required to satisfy the mutated fetal CaSR, suppress PTH gene expression, and prevent hyperplasia in the fetal parathyroid glands. In our case, the missense mutation of the infant was not found in the mother. Therefore, presumed paternal inheritance or a de novo mutation may have contributed to the unusually severe presentation.
Prematurity can modify the expected phenotype of neonatal hyperparathyroidism (NHPT) to one more similar to NSHPT. Such a case has been reported previously of an infant born at 27 weeks gestation with moderate hypercalcemia and severe bone disease who was found to have an inactivating mutation (R220W) of CaSR. The infant received serial pamidronate infusions and two parathyroidectomies in an attempt to control the hypercalcemia, but ultimately succumbed to respiratory disease . Because the fetal skeleton depends heavily on maternal calcium and phosphorus transfer during the third trimester, prematurity predisposes an infant to deficient bone mineral accrual. An inactivated CaSR in this setting could lead to further demineralization of an already weakened skeleton and potentially lead to more severe skeletal findings. In addition, the CaSR is expressed in the placenta. Mice studies of inactivating CaSR mutations have found decreased transfer of calcium to the fetus. Theoretically, this could lead to an additional stimulus for fetal PTH secretion.
Maternal vitamin D deficiency
Maternal vitamin D deficiency with a negative calcium balance has been suggested to cause stimulation of fetal parathyroid glands in utero . The 25(OH)D3 in the infant obtained soon after presentation was within the normal range. The mother’s level at delivery is unknown but considering the prevalence of vitamin D deficiency in New England  and the fact that this child was born in March, it is plausible that some degree of maternal D insufficiency was involved in the pathogenesis of hyperparathyroidism in this patient, although likely to a small degree.
After 2–3 months of cholecalciferol treatment, the skeletal findings resolved and the biochemical parameters more closely corresponded to the classical features seen in FHH. The infant had a combination of mild hypercalcemia, mildly elevated serum magnesium, inappropriately high-normal PTH and low urinary calcium creatinine clearance .
Postnatally, the CaSR is not widely expressed in renal tubular cells but its expression increases over the first several months leading to enhanced calcium reabsorption and declining urinary calcium excretion in the normal infant . In our infant, the calcium/creatinine clearance ratio (CCCR) was strikingly low throughout her course and consistently in the range seen in FHH which is <0.02 . Despite resolution of the severe hyperparathyroidism over the infant’s first 3 months, her PTH continued to be in the high normal range despite increasing cholecalciferol dosing. This might indicate a more severe than average course, since persistent elevation of PTH is reported only in 20% of cases of FHH . In addition, CaSR mutations are associated with adenomatous primary hyperparathyroidism .
We elected to use cholecalciferol to try to hasten the resolution of the hyperparathyroidism because of the active bone disease. Within the parathyroid glands, local conversion of 25(OH)D3 to 1,25(OH)2 D3 has been suggested as an independent factor modulating CaSR and PTH production . 1,25(OH)2 D3 is known to regulate PTH and CaSR gene expression as well as parathyroid cell growth . Vitamin D has been shown to help decrease PTH levels in primary and secondary hyperparathyroidism  and has been used in the treatment of clinically significant FHH . Our experience showed that cholecalciferol treatment was safe. Potentially it may have supported the infant in achieving the elevated threshold for calcium-sensing of the mutated CaSR, but its role in moderating symptomatic FHH or altering the natural course of FHH has to be further investigated. Another medical treatment option for cases such as this would be calcimemetics like cinacalcet. This agent activates the CaSR through binding to the seven transmembrane domain of the CaSR and has been shown to improve the sensitivity of the parathyroid glands to calcium and to treat hyperparathyroidism . Since there is significant genetic heterogeneity in FHH, calcimemetics might not render equivalent effects in different types of CaSR mutations. One might consider using a calcimemetic in the future if the persistent hyperparathyroidism and hypercalcemia leads to complications.