NSHPT (OMIM #239200) is caused most commonly by homozygous or compound heterozygous loss- of- function mutations in the CASR. NSHPT is typically a life- threatening disorder in early infancy, if left untreated. Newborns with NSHPT usually suffer from severe hypercalcaemia with levels as high as 7.7 mmol/ L reported (normal range for a full- term newborn with birth weight over 1500 g, 2.10– 2.65 mmol/ L), marked (5- to- 10- fold) elevations of serum PTH concentrations, enlarged parathyroid glands, hypotonia, respiratory distress, and hyperparathyroid bone disease leading to bone deformities and multiple fractures. Without functioning CaSRs in the parathyroid glands, PTH is not sup pressed even at these very high serum calcium levels. If the mutant CaSR retains some capacity to signal, PTH might be suppressed but to a very limited degree. Emergent parathyroidectomy is usually required and lifesaving. More than 25 different mutations are associated with NSHPT, of which more than 40% are either non sense or frameshift mutations, that lead to a truncated CaSR. Often neonates with NSHPT are born to parents who are first- degree relatives and who both have FHH and the same mutation in the CASR. This leads to the homozygous form of the disease (NSHPT) in an offspring with both alleles affected identically. NSHPT has also been described in a neonate with compound heterozygous mutations— one in each CASR allele. Since such neonates (with either homozygous or compound heterozygous mutations) have no or very low levels of normal CaSRs, these infants present with severe hypercalcaemia and typically (but not always) will require urgent parathyroidectomy. Not every patient with homozygous inactivating mutation of the CASR suffers from NSHPT. One patient was described who was homozygous for a p.P39A mutation in the CaSR and was only identified in adulthood, despite serum calcium levels of 3.74– 4.24 mmol/ L. When the mutation was studied in vitro, it displayed only mild functional impairment. Another patient presented at age 2 with moderate hypercalcaemia and fractional excretion of calcium below 0.01. Genetic analysis of the CASR in that case demonstrated a homozygous p.Q459R mutation within the ECD of the receptor. The patient displayed an autosomal recessive inheritance pattern. All affected individuals in the family who were heterozygous for the mutation were normocalcaemic, although in the upper range of normal. Unaffected individuals had serum calcium levels which were significantly lower.
Some infants with only a mild impairment of CaSR function, due to the presence of compound heterozygous CASR mutations, develop instead neonatal hyperparathyroidism (NHPT). These infants present with symptomatic hypercalcaemia and often fail to thrive. This presentation seems to occur instead of classical FHH (mild asymptomatic hypercalcaemia often discovered incidentally) due to additional environmental and/ or genetic factors that result in fetal calcium deficiency. Infants with NHPT may show less elevated but more symptomatically transient hypercalcaemia than the dramatic presentations of NSHPT. They may further show moderate to severe elevations in PTH and hyperparathyroid bone disease. Following conservative treatment, some infants even transition to the more asymptomatic form of FHH and have not even required parathyroid surgery. Factors contributing to a more severe phenotype in utero include gestation in an unaffected mother or coexistence of maternal vitamin D deficiency, which can worsen the degree of hyperparathyroidism. The neonate might also experience a dominant- negative effect of an abnormal CASR gene on the remaining normal allele, due to CaSR surface dimerization. When a mutant receptor is coexpressed with the wild- type CaSR in vitro, the affinity for calcium may be reduced, possibly due to the abnormally functioning heterodimers that can form under such conditions. Sequence analysis of the CASR will help to distinguish NSHPT and NHPT.
Before parathyroid surgery, bisphosphonates and the calcimimetic cinacalcet have been used in newborns to treat severe hypercalcaemia and slow bone demineralization. The response to cinacalcet is de pendent on the underlying CASR mutation. If cinacalcet can bind to the mutated CaSR as a positive allosteric modulator, it can often improve CaSR signalling associated with many loss- of- function mutations and improve hypercalcaemia and bone mineralization. However, in infants with NSHPT due to biallelic truncating CASR mutations, for example, cinacalcet has been shown to be in effective, due to the inability of the drug to bind to the CaSR and/ or couple to downstream signalling pathways.
Hypercalcaemia After infancy and Primary Hyperparathyroidism (PHPT) in Patients With FHH Cases have been reported in which loss- of- function CASR mutations become apparent in childhood or early adulthood, often because of pronounced hypercalcaemia. Homozygous loss- of- function mutations at the N- terminal region of the CaSR have led to symptomatic hypercalcaemia after infancy and required parathyroidectomy. Patients with PHPT due to parathyroid adenomas or hyperplasia have even been diagnosed with heterozygous or homozygous loss- of- function CASR mutations. Homozygous CASR mutations in these adult- onset PHPT patients seem to affect extra cellular calcium- sensing and intracellular calcium signalling less compared to homozygous mutations in infants with NSHPT. CASR mutations located in the ECD of the receptor in patients with PHPT or severe FHH are associated with more pronounced hypercalcaemia and multigland disease. Surgical treatment might therefore require a four- gland rather than a focused minimally invasive parathyroid exploration.
