Neonatal severe hyperparathyroidism (NSHPT)

NSHPT presents at birth or during the first months of life with severe, potentially life-threatening hypercalcaemia, markedly elevated parathyroid hormone (PTH) concentrations, diffuse parathyroid hyperplasia and relative hypocalciuria. Skeletal manifestations are prominent and include generalised bone demineralisation, metaphyseal widening, osteitis fibrosa and pathological fractures. Affected neonates commonly present with hypotonia, respiratory distress, failure to thrive, dehydration, lethargy, and gastrointestinal dysmotility.

If untreated, the disease may result in significant neurodevelopmental impairment and is associated with a high mortality. Total parathyroidectomy leads to permanent requiring lifelong replacement therapy, distinguishing the long-term course from milder CaSR-related disorders.

NSHPT is most commonly inherited in an autosomal recessive manner. Both parents are typically heterozygous carriers of a pathogenic CASR variant and often exhibit the biochemical phenotype of type 1 (FHH1), although they are frequently asymptomatic. For couples in whom both partners carry a pathogenic CASR variant, the recurrence risk for each pregnancy is 25%. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

NSHPT is suspected based on characteristic clinical, biochemical and radiological findings and is confirmed by molecular genetic testing. Biochemical findings include severe hypercalcemia, markedly elevated parathyroid hormone concentration, and relative hypocalciuria. Radiographic evaluation may demonstrate generalised bone demineralisation, metaphyseal widening, osteitis fibrosa and pathologic fractures, while renal ultrasound may reveal nephrocalcinosis. Identification of pathogenic loss-of-function variants in CASR, most commonly biallelic variants, confirms the diagnosis and distinguishes NSHPT from familial hypocalciuric hypercalcaemia (FHH) and other causes of neonatal hypercalcaemia.

Main differential diagnoses include:

• type 1 (FHH1): mild-to-moderate hypercalcaemia with hypocalciuria persisting from infancy, typically asymptomatic, calcium-to-creatinine clearance ratio <0.01, usually monoallelic loss-of-function variants; CASR
• Primary hyperparathyroidism (PHPT): later-onset (usually adult) hypercalcaemia with elevated PTH due to parathyroid adenoma or hyperplasia, calcium-to-creatinine clearance ratio ≥0.02, no biallelic CASR loss-of-function; MEN1, CDC73, RET, CDKN1B, e.g.
• Transient neonatal hyperparathyroidism: self-limited neonatal hypercalcaemia in an infant with a monoallelic CaSR loss-of-function variant born to a normocalcaemic mother, or secondary to maternal hypocalcaemia; CASR, TRPV6

• Establishing the diagnosis at the molecular level allows the underlying genetic cause to be identified and confirmed.
• Identification of the causative variant supports individualised clinical management of affected individuals, which is decided by the treating physicians in consultation with the affected individual and their family.
• Once the familial pathogenic variants have been identified, targeted testing of at-risk relatives is technically possible and may inform reproductive counselling.

• Papadopoulou A, Bountouvi E, Karachaliou FE. The molecular basis of calcium and phosphorus inherited metabolic disorders. Genes (Basel). 2021;12(5):734. PMID: .
• Özgüç Çömlek F, Demir S, Gürkan H, İnan M, Sezer A, Dilek E, et al. The efficiency of cinacalcet treatment in delaying parathyroidectomy in a case with neonatal severe hyperparathyroidism caused by homozygous mutation in the CASR gene. Pediatr Endocrinol Diabetes Metab. 2022;28(2):168-174. PMID: .
• Minisola S, Arnold A, Belaya Z, Brandi ML, Clarke BL, Hannan FM, et al. Epidemiology, pathophysiology, and genetics of primary hyperparathyroidism. J Bone Miner Res. 2022;37(11):2315-2329. PMID: .