Neonatal severe hyperparathyroidism

Neonatal severe primary hyperparathyroidism (NSHPT) is characterized by severe hypercalcemia (> 3.5 mM) from birth and associated with major hyperparathyroidism. The clinical manifestations are early (with onset occurring during the first days of life) and severe, including respiratory distress due to hypotonia and rib cage deformities, bone under mineralization, and multiple fractures, all of which influence the immediate vital prognosis.

Cause

NSHPT is associated in most cases with homozygous inactivating mutations in the CASR gene, localized to 3q21.1. This gene encodes the calcium-sensing receptor (CaSR), a member of the subfamily of G protein-coupled transmembrane receptors. CaSR plays a key role in the regulation of phosphocalcic metabolism by controlling parathyroid hormone (PTH) secretion and calcium urinary excretion in response to variations in serum calcium levels.

Inheritance

NSHPT represents the homozygous form of FHH and is transmitted as an autosomal recessive trait. However, sporadic forms of NSHPT occur and are associated with a heterozygous de novo mutation in the CASR gene. To date, there have been no reports of severe neonatal hyperparathyroidism with homozygous mutations in those with FHH type 2 or 3 (see these terms) but their molecular identification is still too recent to make any definite conclusions.

Symptoms

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal calcium-phosphate regulating hormone level
• Abnormality of the metaphysis(Abnormality of the wide portion of a long bone)
• Abnormality of the thyroid gland(Thyroid abnormality)
• Aminoaciduria(High urine amino acid levels)
• Hepatomegaly(Enlarged liver)
• Muscular hypotonia(Low or weak muscle tone)
• Narrow chest(Low chest circumference)
• Recurrent fractures(Increased fracture rate)
• Short stature(Decreased body height)
• Splenomegaly(Increased spleen size)

Diagnostic methods

Biologically, children present with extremely high serum calcium and serum PTH levels and a relative hypocalciuria, but in some cases they present with a markedly elevated calciuria.

Differential diagnosis

Familial hypocalciuric hypercalcemia (FHH; see this term) is a differential diagnosis. Hypercalcemia is usually milder and PTH levels are lower in FHH than in NSHPT and FHH is asymptomatic in most cases.

Antenatal diagnosis

Prenatal diagnosis might be proposed to parents if they are both suffering from FHH.

Treatment

The control of hypercalcemia is often obtained through progressive therapeutic intervention involving the use of bisphosphonates, dialysis or even calcimimetics. If this is unsuccessful, a total parathyroidectomy is required. After parathyroidectomy, life-long treatment with 1-alpha hydoxylated vitamin D is required. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Cinacalcet (Brand name: Sensipar®)Treatment of hypercalcemia in adult patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy.

Prognosis

Patients can die from complications of hypercalcemia during the neonatal period from respiratory distress and dramatic hypercalcemia.

NIH genetic and rare disease info

• NIH info on Neonatal severe hyperparathyroidism

Neonatal severe hyperparathyroidism is a rare disease.

Neonatal severe hyperparathyroidism Resources
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