Neonatal severe hyperparathyroidism (NSHPT)

(OMIM phenotype number #239200)

Neonatal severe hyperparathyroidism is a rare autosomal recessive disorder of calcium homeostasis. NSHPT occurs in the first 6 months of life, but is often discovered in the first few weeks postnatally. Homozygous CASR germline pathogenic variants are classically associated with NSHPT. The CaSR gene encodes the calcium-sensing receptor (CaSR), a G protein-coupled receptor that is highly expressed in the parathyroid and kidney. The inactivating mutations of CaSR gene reduce the sensitivity of the CaSR to extracellular calcium, with consequent increased parathyroid secretion of PTH and decreased renal excretion of calcium. NSHPT is characterized by parathyroid hyperplasia, marked and symptomatic PTH-dependent hypercalcemia, relative hypocalciuria, and bone fragility. Early radiologic features include: bony demineralization, pathologic fractures of long bones and ribs, subperiosteal resorption, rib fractures and rachitic changes. Infants with NSHPT often exhibit polyuria, dehydration and hypotonia associated with a history of failure to thrive, respiratory distress, irritability, lethargy, constipation, and delayed neuropsychological development. All these clinical manifestations are more evident if HPT is not promptly treated. NSHPT can be fatal if partial or total parathyroidectomy is not carried out within the first several weeks of life, with a good short-term prognosis after surgery and rapid involution of bony abnormalities.

Intravenous aminobisphosphonates are used in NSHPT to control severe hypercalcemia prior parathyroidectomy or as a rescue therapy to stabilise life-threatening demineralization. Recently, Gannon AW et al. have described the first use of cinacalcet as monotherapy for severe hypercalcemia in a newborn affected by NSHPT, showing a rapid and durable response to cinacalcet.

Gene

CaSR gene, 3q21.1 (OMIM gene/locus number +601199).

Phenotype

Life-threatening, severe osteoporosis.

Main biochemical alterations

Extremely high Ca, high Ur Ca, low Pi, high Ur Pi, high PTH.

Images

Fig. Radiographs of the patient affected by NSHPT demonstrating diffuse demineralization (A), multiple rib fractures (arrows), and chondrodystrophy of the distal humerus (B) and femur (C). A butterfly vertebrae was also noted on the chest radiograph.

Reproduced from J Clin Endocrinol Metab 99;1:7-11 under the terms of the Creative Commons Attribution License (CC BY).

 



References

  1. Al-Khalaf FA, Ismail A, Soliman AT, Cole DE, Ben-Omran T. Neonatal severe hyper- parathyroidism: further clinical and molecular delineation. Eur J Pediatr 2011;170: 625–31.
  2. Hendy GN, Guarnieri V, Canaff L. Calcium-sensing receptor and associated diseases. Prog Mol Biol Transl Sci 2009;594:31–95.
  3. Bai M, Pearce SH, Kifor O, Trivedi S, Stauffer UG, Thakker RV, et al. In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, hetero- zygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium ho- meostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia. J Clin Invest 1997;99:88–96.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Nov;26(11):2717-8.
  5. http://www.omim.org